Sertraline-Induced Pseudocholinesterase Enzyme Deficiency

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Open Access Full Text Article Case report Sertraline-induced pseudocholinesterase enzyme deficiency

Beyazit Zencirci Abstract: A 47-year-old Turkish male was scheduled for laparoscopic cholecystectomy under MOSTAS Private Health Hospital, general anesthesia. The patient had 2 operations 28 and 19 years ago under general anesthesia. Department of Anesthesiology, It was learned that the patient was administered succinylcholine during both of these previous Kahramanmaras, Turkey operations and that he did not have a history of prolonged recovery or postoperative apnea. The patient had been using sertraline for 3 years before the operation. Pseudocholinesterase is a drug-metabolizing enzyme responsible for hydrolysis of the muscle-relaxant drugs mivacurium and succinylcholine. Deficiency of this enzyme from any cause can lead to prolonged apnea and paralysis following administration of mivacurium and succinylcholine. The diagnosis of pseudocholinesterase enzyme deficiency can be made after careful clinic supervision and

For personal use only. peripheral nerve stimulator monitoring. A decrease in the activity of pseudocholinesterase enzyme and a decline in the block effect over time will help verify the diagnosis. Our patient’s plasma cholinesterase was found to have low activity. Instead of pharmacological interventions that may further complicate the situation in such cases, the preferred course of action should be to wait until the block effect declines with the help of sedation and mechanical ventilation. In our case, the prolonged block deteriorated in the course of time before any complications developed. Keywords: mivacurium, pseudocholinesterase deficiency, sertraline

Introduction Pseudocholinesterase (PCHE) is an enzyme with a complex molecular structure.1 It is synthesized in the liver and immediately released into the plasma.2 The plasma half-life 3 International Journal of General Medicine downloaded from https://www.dovepress.com/ by 54.191.40.80 on 02-Jul-2017 has been estimated to be approximately 12 days. Deficiency or reduced activity of this enzyme results in significant prolongation of mivacurium- or succinylcholine-induced neuromuscular blockade.4 In addition, a number of disease states or concomitant drug administration may reduce PCHE activity. Mivacurium, which is a nondepolarizing neuromuscular blocking drug administered in doses of 0.1 to 0.2 mg/kg, also produces rapid onset of neuromuscular blockade lasting for 15 to 30 minutes.5 The rapid ester hydrolysis of mivacurium by PCHE results in the short duration of action of this drug, which is ideal for providing muscle relaxation for brief surgical procedures.6 But the duration of mivacurium of action in Correspondence: Beyazit Zencirci adults is inversely related to serum PCHE activity.7,8 M. Akif Inan Mah. Alparslan Turkes Sertraline is an antidepressant and antipanic agent that is a potent and selective Bulvari, Seyhan Apt. No: 209 D: 5, Merkez-Kahramanmaras, Turkey inhibitor of serotonin reuptake into the presynaptic terminals. It has relatively weak Tel +90 344-2258300 effects on the cytochrome P450 system, a tolerability profile that is positive compared Fax +90 344-2258303 Email [email protected] with antidepressants of other classes, and it is relatively safe in overdose. These findings

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contribute to sertraline being the first-line agent for the and ventilator support. Spontaneous muscle twitching was treatment of several psychiatric disorders.9 It was shown, noted 2 hours and 20 minutes later. Train-of-four response however, that sertraline and other antidepressants inhibited ratio was 75% 2 hours and 55 minutes after mivacurium acetylthiocholine hydrolysis by cholinesterases in human administration. serum and erythrocyte membrane.10 The patient regained sufficient motor function to meet In this article, we share our experience of a case with extubation requirements 3 hours and 15 minutes after the acquired pseudocholinesterase enzyme deficiency due to initial use of mivacurium. Midazolam infusion was dis- sertraline use, and provide a literature review. continued and clinical assessment confirmed recovery of neuromuscular function. The patient was extubated for Case report* 205 minutes following the administration of mivacurium A 47-year-old Turkish male, 83 kg in weight and 175 cm in and further recovery was uneventful. Plasma cholinesterase height, was scheduled for laparoscopic cholecystectomy (due was found to have very low activity (788 IU/L). The patient to cholecystitis with an acute stone) under general anesthesia. was transferred to a hospital ward for the evening and was Under general anesthesia, the case had an appendectomy discharged 4 days later. 28 years ago and a right inguinal hernia operation 19 years ago. It was learned that the patient was administered suc- Discussion cinylcholine during both these operations and that he did Mivacurium is a potent benzylisoquinoline, nondepolarizing, not have a history of prolonged recovery or postoperative neuromuscular blocking drug. A recommended intravenous apnea. Except for alkaline phosphatase (ALP) (176 U/L), dose of 0.15 to 0.2 mg/kg provides tracheal intubating con- alanine aminotransferase (ALT) (52 U/L) and a minimal ditions within 2 to 2.5 minutes, with a predicted duration of increase in aspartate aminotransferase (AST) (61 U/L), and action of 15 to 25 minutes, making it an ideal drug for short a slight leucocytosis (9.8 × 109/L), no other pathologies were procedures requiring tracheal intubation.11 It is a structural identified during preoperative laboratory investigation. The relative of atracurium, but it does not undergo Hofmann For personal use only. patient had been using sertraline (100 mg/day) for 3 years elimination and is rapidly hydrolyzed by PCHE. The activity for major depressive disorder. of PCHE affects its duration of action.4 Following preoxygenation, induction of anesthesia was PCHE is a tetrameric glycoprotein enzyme produced by achieved with 200 mg of propofol. Tracheal intubation the liver, which hydrolyzes choline esters such as those found was achieved with 17 mg of mivacurium. Isoflurane was in succinylcholine, mivacurium, procaine, chloroprocaine, used as the general anesthetic inhalation agent. The operation tetracaine, cocaine, and heroine.12 In patients with a normal lasted for 30 minutes and the surgery was uneventful. After genotype for PCHE, mivacurium’s duration of action is surgery, the inhalation agent was discontinued, the patient inversely related to PCHE activity and duration of action is received 100% oxygen but there was no clinical evidence of slightly prolonged if activity is low.13 neuromuscular function recovery and there was no response When there is a deficiency of this enzyme due to the to train-of-four stimulation. Peripheral nerve stimulator presence of one or more atypical alleles, mivacurium is not

International Journal of General Medicine downloaded from https://www.dovepress.com/ by 54.191.40.80 on 02-Jul-2017 (PNS) produced zero twitches. Anesthesia was therefore properly metabolized and thus muscle paralysis can last maintained with 0.5% isoflurane in 50% nitrous oxide for several hours. There are 2 forms of inherited atypical and oxygen because there was no evidence of improved pseudocholinesterase deficiency. The heterozygous atypical neuromuscular function 50 minutes after administration form affects from 1 in 25, to 1 in 480 individuals (depending of mivacurium. All vital signs were stable, and oxygen on the severity of the condition).12 Patients heterozygous for saturation remained 100%. After an additional 20 minutes, an abnormal enzyme may show up to 50% prolongation of a PCHE deficiency was suspected. Five milligrams of block.13 In patients homozygous for an abnormal enzyme, midazolam was administered intravenously for its seda- duration may be significantly prolonged, and even a small tive and amnestic effects. Later the patient was transferred dose (eg, 0.03 mg/kg) can result in complete paralysis for to the Post-anesthesia Care Unit (PACU) for observation up to 128 minutes.14 There are now several case reports in the literature of prolonged block following mivacurium *Monitoring included electrocardiography (ECG), noninvasive arterial administration.

blood pressure (NIBP), oxygen saturation (SpO2), capnography (ETCO2), and peripheral nerve stimulator (PNS) monitoring applied over the ulnar Different disease states and/or drug administrations nerve in this case. may affect PCHE activity. Physiological reductions may

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occur with extremes of age and during pregnancy.15 Other Consequently, undesirable pharmacological and toxicological acquired causes of decreased activity include renal and liver side effects of these antidepressants can be related, at least in disease, malignancy, burns, chronic debilitation/malnutrition, part, to inhibition of serum and erythrocyte cholinesterases.10 myocardial infarction/cardiac failure, collagen diseases, Therefore, chronic enzyme inhibition which might have myxedema, and organophosphate poisoning.16 Plasma developed due to 3 years of use of sertraline in our patient cholinesterase levels in human subjects with protein energy led to a significant and marked prolongation in the activity malnutrition have been investigated.17 time of the neuromuscular blocking agent metabolized by Drugs that inhibit the enzyme’s activity include ace- this enzyme. tylcholinesterase inhibitors (neostigmine, pyridostigmine, The results achieved by Müller et al10 corroborated our physostigmine, and edrophonium), anticholinesterases (espe- suspicions about sertraline. Also, the retested (3 months after cially echothlophate), cytotoxic agents (such as cyclophosph- the operation) PCHE value (2762 IU/L) was seen to have amide), steroids, ester-type local anesthetics, hexafluorenium, returned to normal after the patient gave up using sertraline pancuronium, and oral contraceptives.18 under the supervision of a psychiatrist. We did not discover Our patient previously had 2 operations under general any case that implied an interaction between sertraline and anesthesia with succinylcholine. However, a prolonged pseudocholinesterase in our literature review, and we believe apnea and low enzyme activity (788 IU/L) was present in this is the first presentation of such a case. the operation reported here. Although the patient had not had When we understood that we were dealing with a case any problems during the previous operations, absence of a of acquired PCHE deficiency, we made our treatment plan. medical history proving the existence of the same problem Our main aim was to administer a supportive treatment to the in close relatives led us to think that this was an acquired patient until enzyme activity returned to normal. Therefore PCHE deficiency. At this stage, we at once started to imple- we did not consider a blood transfusion (considering the risks ment an algorithm which is usually used in cases of PCHE of blood transfusion, such as allergic reactions, infection, deficiency. At this stage, we also started to examine the fever reaction). We also avoided administering drugs (such For personal use only. causes of acquired PCHE deficiency thoroughly. However, as calcium, neostigmine) that might complicate the pres- we noted that the medical conditions (such as extremes ent condition. The clinician should be especially aware of age, pregnancy) and problems (such as renal and liver that administering neostigmine to a patient with prolonged disease, malnutrition) reported in the literature that we have mivacurium-induced block will inhibit plasma cholinesterase tried to summarize above did not match our case. Therefore, activity. Therefore, blood should not be drawn for cholinest- we considered the drugs known to affect PCHE activity that erase activity until the effect of neostigmine dissipates. In the patient may have been taking. We discovered that the our case, when we suspected PCHE deficiency, together with patient had been using sertraline (100 mg/day) for 3 years PNS findings, we sent the blood samples to the laboratory for due to depression. enzyme analysis. Consequently, we supported our case solely Sertraline is a serotonin reuptake inhibitor (SSRI) that is with sedation, mechanical ventilation, and PNS monitoring, indicated for the treatment of depression. With therapeutic and without neostigmine application.

International Journal of General Medicine downloaded from https://www.dovepress.com/ by 54.191.40.80 on 02-Jul-2017 doses, side effects are minimal. Sertraline has a wide therapeutic index and appears to be safer than the tricyclic anti- Conclusion depressants in overdose.19 The usual clinical antidepressants Prolonged blocks may be encountered as a result of PCHE (fluoxetine, sertraline, and amitriptyline) are, however, inhibi- enzyme deficiency when mivacurium is used. In our case, tors of the cholinesterases in human serum and erythrocyte this situation was due to sertraline, which is commonly membrane. Antidepressants exhibit this inhibiting effect by administered for various psychiatric disorders, particularly reversibly attaching to the enzyme’s bottom of the active site depression. gorge, and the collapse of the product (eg, mivacurium or In this context, we believe two issues should be high- succinylcholine) being hydrolyzed by the enzyme decreases lighted. Firstly, while examining the drugs used by patients during this process of attachment.10 The order of inhibitory during preoperative anesthesia anamnesis, next-generation potency was sertraline . amitriptyline .. fluoxetine. The antidepressants (especially SSRIs) should not be ignored. As concentrations of antidepressants necessary to inhibit serum in the case reported, this group of drugs, known to have a cholinesterase are relatively close to the clinical levels found wide safety margin, may cause casual and unexpected block after pharmacological use of sertraline and amitriptyline. prolongation when used along with drugs (mivacurium and

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succinylcholine) that are hydrolyzed especially by PCHE 7. Petersen RS, Bailey PL, Kalameghan R, Ashwood ER. Prolonged activity during anesthesia. neuromuscular block after mivacurium. Anesth Analg. 1993;76: 194–196. Secondly, in these situations, attempted reversal of the 8. Goudsouzian NG, d’Hollander AA, Viby-Mogensen J. Prolonged neu- block was at best only partially successful, and the patients romuscular block from mivacurium in two patients with cholinesterase deficiency. Anesth Analg. 1993;77:183–185. were partially paralyzed and minimally sedated while 9. MacQueen G, Born L, Steiner M. The selective serotonin reuptake attempts were made to have them breathe – a very unpleas- inhibitor sertraline: its profile and use in psychiatric disorders. ant experience. In cases of prolonged block, no reversal was CNS Drug Rev. 2001;7:1–24. 10. Müller TC, Rocha JB, Morsch VM, Neis RT, Schetinger MR. Antide- attempted. The patients were kept sedated, and their lungs pressants inhibit human acetylcholinesterase and butyrylcholinesterase mechanically ventilated until the block recovered spontane- activity. Biochim Biophys Acta. 2002;1587:92–98. 11. Frampton JE, McTavish D. Mivacurium. A review of its pharmacol- ously, and then extubated without problem. ogy and therapeutic potential in general anaesthesia. Drugs. 1993;45: 1066–1089. 12. Pantuck E. Plasma cholinesterase: gene and variations. Anesth Analg. Disclosure 1993;77:380–386. The author reports no conflicts of interest. 13. Ostergaard D, Jensen FS, Jensen E, Skovgaard LT, Viby-Mogensen J. Influence of plasma cholinesterase activity on recovery from mivacurium-induced neuromuscular blockade in phenotypically normal patients. References Acta Anaesthesiol Scand. 1992;36:702–706. 1. Lockridge O, Bartels CF, Vaughan TA, Wong CK, Norton SE, Johnson LJ. 14. Ostergaard D, Jensen FS, Jensen E, Skovgaard LT, Viby-Mogensen J. Complete amino acid sequence of human serum cholinesterase. J Biol Mivacurium-induced neuromuscular blockade in patients with atypical Chem. 1987;262:549–557. plasma cholinesterase. Acta Anaesthesiol Scand. 1993;37:314–318. 2. Pedersen NA, Jensen FS. Clinical importance of plasma cholinesterase for 15. Jensen FS, Viby-Morgensen J, Ostergaard D. Significance of plasma the anaesthetist. Ann Acad Med Singapore. 1994;23 Suppl:120–124. cholinesterase for the anaesthetist. Curr Anaesth Crit Care. 1991;2: 3. Ostergaard D, Viby-Mogensen J, Hanel HK, Skovgaard LT. Halflife of 232–237. plasma cholinesterase. Acta Anaesthesiol Scand. 1988;32:266–269. 16. Davis L, Britten JJ, Morgan M. Cholinesterase. Its significance in 4. Cerf C, Mesguish M, Gabriel I, Amselem S, Duvaldestin P. Screening anaesthetic practice. Anaesthesia. 1997;52:244–260. patients with prolonged neuromuscular blockade after succinylcholine 17. Kumari R, Rao YN, Talukdar B, Agarwal S, Puri RK. Serum enzyme and mivacurium. Anesth Analg. 2002;94:461–466. abnormalities in protein energy malnutrition. Ind Pediatr. 1993;30: 5. Ali HH, Savarese JJ, Embree PB, et al. Clinical pharmacology of miva- 469–473. For personal use only. curium chloride (BW B1090U) infusion: comparison with vecuronium 18. Hunter JM. Muscle function and neuromuscular blockade. In: Aitkenhead and atracurium. Br J Anaesth. 1988;61:541–546. AR, Rowbotham DJ, Smith G, editors. Textbook of Anesthesia 4th ed. 6. Savarese JJ, Lien CA, Belmont MR, Wastila WB. The clinical pharmacol- Spain; Churchill Livingstone; 2001:223–237. ogy of new benzylisoquinoline-diester compounds. with special consider- 19. Klein-Schwartz W, Anderson B. Analysis of sertraline-only overdoses. ation of cisatracurium and mivacurium. Anesthetist. 1997;46:840–849. Am J Emerg Med. 1996;14:456–458. International Journal of General Medicine downloaded from https://www.dovepress.com/ by 54.191.40.80 on 02-Jul-2017

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